Lebel and Mes-Masson (1994 DNA Seq 5:31-39) describe a cDNA derived from MT-PVLT-10 transgenic mice, the males of which develop testicular tumors at advanced ages. The mouse cDNA hybridizes to a 2.6 kilobase mRNA which is expressed in various other tissues including liver, testes, and brain. In immortalized cell lines derived from testicular tumors, the expression of this mRNA is approximately two to fifteen times higher than in similar cell lines derived from pre-adenomatous testes. The mouse cDNA consists of a coding region of 1179 nucleotides which predicts a polypeptide of 393 amino acids with an estimated molecular weight of 44.3 kD.
A developmentally regulated gene, designated TPO-1, has been sequenced by Pfeiffer (1993, unpublished). TPO-1 is related to the induced mouse testicular tumor sequence and is expressed during the transition from oligodendroblast to oligodendrocyte in the telencephalon of newborn Sprague-Dawley rats. The open reading frame, nucleotides 156-1538 within the 5395 bp mRNA, encodes a 459 amino acid polypeptide.
Another related protein, Diff 33, is expressed in trophoblast cells from human placenta (Dakuor J et al (1996) unpublished). The 1746 base mRNA contains an open reading frame, nucleotides 107-1591, which encode a polypeptide of 494 amino acid residues which also has homology to the induced mouse testicular tumor sequence.
Differentiation genes, such as Diff 33, have been described in various animal systems. Vielkind (1976, J Exp Zoology 196:197-204) was one of the first scientists to describe the activity of one of the differentiation genes in platyfish-swordtail melanomas. In this case, the differentiation gene appeared to promote the conversion of melanoma cells to melanocytes. Vieland suggested that the dosage of Diff was important in the genetic control of the cell differentiation process. In 1989, Schwab (IARC Sci Publ 239-54) extended that same concept by reporting that Diff works through genetic suppression of oncogenes by controlling the terminal differentiation of cells. More recently, Raza A et al (1993; Am J Hematol 42:147-57) have described the expression of Diff in the long term survival of patients of acute myeloid leukemia. They suggest that the ability to monitor Diff expression has both clinical and prognostic significance.
Discovery of new molecules related to or in the Diff gene family is useful for developing diagnostic or therapeutic compositions directed at melanomas and other forms of cancer. The overexpression of the gene in or the ability to supply the protein to cancerous cells has the potential to suppress relevant oncogenes or to force terminal differentiation thereby stopping cell division and growth of the cancerous cells.